EARLY VERSUS LATE INITIATION OF DIRECT ORAL ANTICOAGULANTS IN POST-ISCHAEMIC STROKE PATIENTS WITH ATRIAL FIBRILLATION (ELAN): AN INTERNATIONAL MULTICENTRE, RANDOMISED-CONTROLLED, TWO-ARM, ASSESSOR-BLINDED TRIAL

Background Prophylactic use of direct oral anticoagulants for recurrent stroke prevention in patients with embolic strokes of undetermined source is currently being investigated. It is uncertain whether the bleeding risks associated with prophylactic direct oral anticoagulants use will outweigh any stroke prevention benefit in embolic strokes of undetermined source patients who lack underlying atrial fibrillation. Methods We determined the proportion of cryptogenic stroke patients in the CRYSTAL atrial fibrillation trial who met inclusion criteria for the NAVIGATE embolic stroke of undetermined source and RE-SPECT embolic stroke of undetermined source trials and their atrial fibrillation incidence. Both embolic strokes of undetermined source trials impose requirements on age, modified Rankin Score, antiplatelet use, and type of infarction. Insertable cardiac monitors were used to determine the atrial fibrillation detection rates at 30 days and 3 years using Kaplan–Meier’s estimates. Results Among 441 patients enrolled in the CRYSTAL atrial fibrillation trial, 189 (42.9%) and 236 (53.5%) met the inclusion criteria of the NAVIGATE embolic stroke of undetermined source and RE-SPECT embolic stroke of undetermined source trials, respectively. Atrial fibrillation detection rates at 3 years among insertable cardiac monitors patients eligible for the NAVIGATE embolic stroke of undetermined source and RE-SPECT embolic stroke of undetermined source trials were 35.8% and 33.6% while detection rates at 30 days were 5.6% and 3.5%, respectively. Conclusion Only half of cryptogenic stroke patients in CRYSTAL atrial fibrillation met the inclusion criteria for the ongoing embolic strokes of undetermined source trials. Approximately, two-thirds of patients with embolic strokes of undetermined source do not have any atrial fibrillation despite continuous rhythm monitoring for up to three years. The benefits of prophylactic use of direct oral anticoagulants in the absence of atrial fibrillation is unknown and therefore embolic strokes of undetermined source patients could benefit from prolonged atrial fibrillation monitoring until more robust data are available. ClinicalTrials.gov Registration NCT00924638. https://clinicaltrials.gov/ct2/show/NCT00924638 .

Download Full-text

Rationale and design of the Registry of Acute Stroke Under Novel Oral Anticoagulants-prime (RASUNOA-prime)

European Stroke Journal ◽

10.1177/2396987318812644 ◽

2018 ◽

Vol 4 (2) ◽

pp. 181-188 ◽

Cited By ~ 2

Author(s):

Kirsten Haas ◽

Jan C Purrucker ◽

Timolaos Rizos ◽

Peter U Heuschmann ◽

Roland Veltkamp

Keyword(s):

Atrial Fibrillation ◽

Ischaemic Stroke ◽

Vitamin K ◽

Intracerebral Haemorrhage ◽

Acute Ischaemic Stroke ◽

Emergency Treatment ◽

Clinical Course ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Stroke Patients

Background Anticoagulation with vitamin K antagonists and non-vitamin K antagonists oral anticoagulants (NOAC) is effective in stroke prevention in patients with atrial fibrillation. However, anticoagulation also poses a major challenge for emergency treatment of patients suffering ischaemic stroke or intracerebral haemorrhage. Aim The registry RASUNOA-prime is designed to describe current patterns of emergency management, clinical course and outcome of patients with atrial fibrillation experiencing an acute ischaemic stroke or intracerebral haemorrhage under different anticoagulation schemes prior to stroke (NOAC, vitamin K antagonists or no anticoagulation). Methods and design RASUNOA-prime (ClinicalTrials.gov, NCT02533960) is a prospective, investigator-initiated, multicentre, observational cohort study aiming to recruit 3000 patients with acute ischaemic stroke and atrial fibrillation, and 1000 patients with acute intracerebral haemorrhage and atrial fibrillation with different anticoagulation schemes pre-stroke. It is a non-interventional triple-armed study aiming at a balanced inclusion of ischaemic stroke and intracerebral haemorrhage patients according to the different anticoagulation schemes. Patients will be followed up for clinical course, management and outcome up to three months after the event. Findings in ischaemic stroke and intracerebral haemorrhage patients on NOAC will be compared with patients taking vitamin K antagonists or no anticoagulant pre-stroke. Study outcomes Primary endpoint for ischaemic stroke patients: occurrence of symptomatic intracerebral haemorrhage, for intracerebral haemorrhage patients: occurrence of secondary haematoma expansion. Secondary endpoints include assessment of coagulation, use of thrombolysis and/or mechanical thrombectomy, occurrence of complications, implementation of secondary prevention. Summary Describing the current patterns of early management as well as outcome of stroke patients with atrial fibrillation will help guide physicians to develop recommendations for emergency treatment of stroke patients under different anticoagulation schemes.

Download Full-text

Burden of oral anticoagulation in embolic stroke of undetermined source without atrial fibrillation

BMC Cardiovascular Disorders ◽

10.1186/s12872-021-01967-x ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Klaus K. Witte ◽

Georgios Tsivgoulis ◽

Matthew R. Reynolds ◽

Stelios I. Tsintzos ◽

Simon Eggington ◽

...

Keyword(s):

Atrial Fibrillation ◽

Ischaemic Stroke ◽

Recurrent Stroke ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Bleeding Event ◽

Cost Savings ◽

Embolic Stroke ◽

Bleeding Events ◽

Event Rates

Abstract Objective Prevention of recurrent stroke in patients with embolic stroke of undetermined source (ESUS) is challenging. The advent of safer anticoagulation in the form of direct oral anticoagulants (DOACs) has prompted exploration of prophylactic anticoagulation for all ESUS patients, rather than anticoagulating just those with documented atrial fibrillation (AF). However, recent trials have failed to demonstrate a clinical benefit, while observing increased bleeding. We modeled the economic impact of anticoagulating ESUS patients without documented AF across multiple geographies. Methods CRYSTAL-AF trial data were used to assess ischaemic stroke event rates in ESUS patients confirmed AF-free after long-term monitoring. Anticipated bleeding event rates (including both minor and major bleeds) with aspirin, dabigatran 150 mg, and rivaroxaban 20 mg were sourced from published meta-analyses, whilst a 30% ischaemic stroke reduction for both DOACs was assumed. Cost data for clinical events and pharmaceuticals were collected from the local payer perspective. Results Compared with aspirin, dabigatran and rivaroxaban resulted in 17.9 and 29.9 additional bleeding events per 100 patients over a patient’s lifetime, respectively. Despite incorporating into our model the proposed 30% reduction in ischaemic stroke risk, both DOACs were cost-additive over patient lifetime, as the costs of bleeding events and pharmaceuticals outweighed cost savings associated with the reduction in ischaemic strokes. DOACs added £5953–£7018 per patient (UK), €6683–€7368 (Netherlands), €4933–€9378 (Spain), AUD$5353–6539 (Australia) and $26,768–$32,259 (US) of payer cost depending on the agent prescribed. Additionally, in the U.S. patient pharmacy co-payments ranged from $2468–$12,844 depending on agent and patient plan. In all settings, cost-savings could not be demonstrated even when the modelling assumed 100% protection from recurrent ischaemic strokes, due to the very low underlying risk of recurrent ischaemic stroke in this population (1.27 per 100 patient-years). Conclusions Anticoagulation of non-AF patients may cause excess bleeds and add substantial costs for uncertain benefits, suggesting a personalised approach to anticoagulation in ESUS patients.

Download Full-text

Atrial fibrillation and stroke: a practical guide

Practical Neurology ◽

10.1136/practneurol-2018-002089 ◽

2019 ◽

Vol 19 (3) ◽

pp. 208-224 ◽

Cited By ~ 7

Author(s):

Jonathan Gordon Best ◽

Robert Bell ◽

Mohammed Haque ◽

Arvind Chandratheva ◽

David John Werring

Keyword(s):

Atrial Fibrillation ◽

Ischaemic Stroke ◽

Interdisciplinary Collaboration ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Stroke Care ◽

Evidence Base ◽

Ongoing Research ◽

Widespread Availability ◽

Difficult Area

Neurologists and stroke physicians will be familiar with atrial fibrillation as a major cause of ischaemic stroke, and the role of anticoagulation in preventing cardioembolic stroke. However, making decisions about anticoagulation for individual patients remains a difficult area of clinical practice, balancing the serious risk of ischaemic stroke against that of major bleeding, particularly intracranial haemorrhage. Atrial fibrillation management requires interdisciplinary collaboration with colleagues in cardiology and haematology. Recent advances, especially the now-widespread availability of direct oral anticoagulants, have brought opportunities to improve stroke care while posing new challenges. This article gives an overview of the contemporary diagnosis and management of atrial fibrillation, and the associated evidence base. Where there is uncertainty, we describe our own approach to these areas, while highlighting ongoing research that will likely guide future practice.

Download Full-text

Early versus late start of direct oral anticoagulants after acute ischaemic stroke linked to atrial fibrillation: an observational study and individual patient data pooled analysis

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2021-327236 ◽

2021 ◽

pp. jnnp-2021-327236

Author(s):

Gian Marco De Marchis ◽

David J. Seiffge ◽

Sabine Schaedelin ◽

Duncan Wilson ◽

Valeria Caso ◽

...

Keyword(s):

Atrial Fibrillation ◽

Ischaemic Stroke ◽

Acute Ischaemic Stroke ◽

Individual Patient Data ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Pooled Analysis ◽

Patient Data ◽

Optimal Timing ◽

Significant Difference

ObjectiveThe optimal timing to start direct oral anticoagulants (DOACs) after an acute ischaemic stroke (AIS) related to atrial fibrillation (AF) remains unclear. We aimed to compare early (≤5 days of AIS) versus late (>5 days of AIS) DOAC-start.MethodsThis is an individual patient data pooled analysis of eight prospective European and Japanese cohort studies. We included patients with AIS related to non-valvular AF where a DOAC was started within 30 days. Primary endpoints were 30-day rates of recurrent AIS and ICH.ResultsA total of 2550 patients were included. DOACs were started early in 1362 (53%) patients, late in 1188 (47%). During 212 patient-years, 37 patients had a recurrent AIS (1.5%), 16 (43%) before a DOAC was started; 6 patients (0.2%) had an ICH, all after DOAC-start. In the early DOAC-start group, 23 patients (1.7%) suffered from a recurrent AIS, while 2 patients (0.1%) had an ICH. In the late DOAC-start group, 14 patients (1.2%) suffered from a recurrent AIS; 4 patients (0.3%) suffered from ICH. In the propensity score-adjusted comparison of late versus early DOAC-start groups, there was no statistically significant difference in the hazard of recurrent AIS (aHR=1.2, 95% CI 0.5 to 2.9, p=0.69), ICH (aHR=6.0, 95% CI 0.6 to 56.3, p=0.12) or any stroke.ConclusionsOur results do not corroborate concerns that an early DOAC-start might excessively increase the risk of ICH. The sevenfold higher risk of recurrent AIS than ICH suggests that an early DOAC-start might be reasonable, supporting enrolment into randomised trials comparing an early versus late DOAC-start.

Download Full-text

Uninterrupted anticoagulation during catheter ablation for atrial fibrillation: no difference in major bleeding and stroke between direct oral anticoagulants and vitamin K antagonists in an updated meta-analysis of randomised controlled trials

Acta Cardiologica ◽

10.1080/00015385.2020.1724689 ◽

2020 ◽

pp. 1-8

Author(s):

Maximilian Brockmeyer ◽

Yingfeng Lin ◽

Claudio Parco ◽

Athanasios Karathanos ◽

Torben Krieger ◽

...

Keyword(s):

Atrial Fibrillation ◽

Catheter Ablation ◽

Major Bleeding ◽

Randomised Controlled Trials ◽

Meta Analysis ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Controlled Trials ◽

Randomised Controlled

Download Full-text

Effectiveness and Safety of Direct Oral Anticoagulants versus Vitamin K Antagonists for People Aged 75 Years and over with Atrial Fibrillation: A Systematic Review and Meta-Analyses of Observational Studies

Journal of Clinical Medicine ◽

10.3390/jcm8040554 ◽

2019 ◽

Vol 8 (4) ◽

pp. 554 ◽

Cited By ~ 11

Author(s):

Anneka Mitchell ◽

Margaret C. Watson ◽

Tomas Welsh ◽

Anita McGrogan

Keyword(s):

Myocardial Infarction ◽

Atrial Fibrillation ◽

Ischaemic Stroke ◽

Major Bleeding ◽

Observational Studies ◽

Intracranial Haemorrhage ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Significant Difference ◽

Meta Analyses

Older people, are underrepresented in randomised controlled trials of direct oral anticoagulants (DOACs) for stroke prevention in atrial fibrillation (AF). The aim of this study was to combine data from observational studies to provide evidence for the treatment of people aged ≥75 years. Medline, Embase, Scopus and Web of Science were searched. The primary effectiveness outcome was ischaemic stroke. Safety outcomes were major bleeding, intracranial haemorrhage, gastrointestinal bleeding, myocardial infarction, and mortality. Twenty-two studies were eligible for inclusion. Two studies related specifically to people ≥75 years but were excluded from meta-analysis due to low quality; all data in the meta-analyses were from subgroups. The pooled risk estimate of ischaemic stroke was slightly lower for DOACs. There was no significant difference in major bleeding, mortality, or myocardial infarction. Risk of intracranial haemorrhage was 44% lower with DOACs, but risk of GI bleeding was 46% higher. Our results suggest that DOACs may be preferable for the majority of older patients with AF, provided they are not at significant risk of a GI bleed. However, these results are based entirely on data from subgroup analyses so should be interpreted cautiously. There is a need for adequately powered research in this patient group.

Download Full-text